Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting.

SHP2, an oncogenic phosphatase pivotal in RAS-MAPK, PI3K-AKT, and JAK-STAT signaling, represents a compelling therapeutic target in malignancies driven by its hyperactivation. While allosteric inhibitors like SHP099 have overcome historical challenges of orthosteric agents by stabilizing SHP2's autoinhibited conformation, opportunities remain to enhance potency, selectivity, and clinical utility. Here, we report a structure-guided expansion strategy leveraging detailed profiling of the tunnel-shaped allosteric pocket to design next-generation inhibitors. Systematic optimization of a pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one scaffold yielded compounds B1 and B8, which exhibit nanomolar enzymatic inhibition (IC = 39 and 15 nM), acceptable pharmacokinetics, and potential oral bioavailability. Strikingly, B8 demonstrated profound synergy with MCL-1 inhibitor VU661013 in acute myeloid leukemia (AML) models, a novel discovery underscoring the therapeutic potential of dual SHP2/MCL-1 targeting. Our work not only advances the rational design of oral allosteric SHP2 inhibitors but also unveils a critical vulnerability in AML through SHP2-MCL-1 co-targeting, offering a roadmap for combinatorial regimens to improve outcomes in high-risk cancers.